L.4 Drug toxicity

Question 1

Drug-Induced Hepatotoxicity

Answer 1

• Acetaminophen is metabolized into NAPQI
  
  • Glutathione conjugate this toxic metabolite before NAPQI attack cellular and mitrochondrial proteins ⇒ resulting in nerosis of hepatocytes
  • NAC is the rescue agent ( IV within 10 hrs of overdose)
• Troglitazone - inihition of the BSEP caused hepatoxicity. ( increased plasma concentration of bile acids)
• serum levels of ALT; ALP, AST and bilirubin are used to monitor for potential hepatoxicity. ALT, ALP and AST are leaked enzymes in the blood stream during hepatocellular injury. Bilirubin builds up due to impaired hepatic function.

Question 2

Drug-Induced Renal Toxicity

Answer 2

• certain antibiotics, NSAIDs, antineoplastic agents, immunomodulators, and (ACE) inhibitors
• Gentamicin causes renal injury by inhibiting lysosomal hydrolases in proximal tubules of the kidney, leading to renal phospholipidosis. This injury is reversible if not too severe, upon cessation of treatment.
• Polyene amphotericin B damages cell membranes –> renal injury to membranes of renal tubular epithelial cells. if not too severe, cessation will result in recovery.
• Contrast media can cause renal injury by direct toxicity and by constriction of the vasa recta → reduced renal medullary blood flow. ( dose-related)

Question 3

Drug-Induced Neurotoxicity

Answer 3

• Peripheral neuropathy has been associated with vinca alkaloids (e.g., vincristine , vinblastine ), taxanes (e.g., paclitaxel ), and platinum compounds (e.g., cisplatin )
• The neuropathy caused by vinca alkaloids and taxanes is directly related to their primary mechanism o action, microtubule disruption
• Platinum-containing compounds may have direct toxic e ects on peripheral nerves. Methotrexate use has been associated with serious toxicity in the CNS (e.g., leukoencephalopathy, seizures).

Question 4

Drug-Induced Skeletal Muscle Toxicity

Answer 4

• HMG-CoA reductase inhibitors ( statins ),
• corticosteroids ( dexamethasone , betamethasone , prednisolone , hydrocortisone)
• zidovudine , and daptomycin .

Question 5

Drug-Induced Cardiovascular Toxicity

Answer 5

• many drugs interact with cardiac potassium channels to cause QTc prolongation, delayed repolarization, and cardiac arrhythmias.
• Second, some drugs are directly toxic to cardiac myocytes.
• some drugs are toxic to heart valves

Question 6

Drug-Induced Pulmonary Toxicity

Answer 6

• Bleomycin and amiodarone are contraindicated in patients with existing disease of the lung parenchyma because both of these agents can cause pulmonary fibrosis.
• Repeated insults to the lung, particularly to the epithelial cells lining conducting airways and alveoli, may be followed by regeneration. Repeated cycles of epithelial injury can also lead to excessive deposition of collagen and extracellular matrix proteins in alveolar septa and the alveolar spaces, causing fibrosis

Question 7

Carcinogenesis Due to Drug Therapy

Answer 7

• initiators : acts by causing specific types of

DNA damage

• by facilitating proliferation of cells carrying precancerous mutations (these agents are promoters )
• Tamoxifen is carcinogenesis

Question 8

Teratogenesis Due to Drug Therapy

Answer 8

retin A, ACE inhibitors can cause teratogenic effect,